This grant has a simple philosophy: a powerful method to approach neurodegenerative disease is (1) use molecular genetics to identify the genes involved in their etiology, with the expectation that these genes will mark a biochemical pathway to disease (2) use the techniques of cell biology and transgenics to try and dissect this pathway and to try and develop cellular and animal models of elements of the disease process. In this proposal, we apply these techniques (predominantly) to Lewy Body Parkinson's disease. It is clear that there are more than three genes involved in the etiology: first, the alpha-synuclein gene, second, an as-yet-unidentified gene on chromosomes 2p and third, an as yet unidentified gene on chromosome 4p: both of these latter two genes have been "linked" by this group. In addition to these known and localized genes, many families do not show linkage to any of the known loci, implying that there are others to be found. With this philosophy and progress as "background", we have the following major aims: Project, to clone the gene on chromosome 4p: Project, to clone the gene on chromosome 2p: Project, to make overexpressing wild type and mutant alpha-synuclein mice with the longterm goal of mimicking parts of the human disease process, and "knockout" mice to aid in the understanding of synuclein function. Projects will encompass similar analyses of the ch4p and ch2p genes and their products as they are identified. These projects will be co-ordinated through an Administrative Core and grouped around a Clinical/pathological Core, which will be responsible for family ascertainment and human blood and brain sample collection and for the pathological verification of diagnosis in both family members and in transgenic animals and a Linkage Core which will be responsible for distributing human family material into four "bins": "mutation Known", "ch4p linked" "ch2p linked and "presently unlinked".